Donald W. Combs

Nonsteroidal progesterone receptor ligands with unprecedented receptor selectivity

We have characterized a series of nonsteroidal progesterone receptor ligands, the tetrahydropyridazines. Compounds in this series, exemplified by RWJ 26819, demonstrate high affinity and unprecedented specificity for the progesterone receptor relative to other steroid hormone receptors. Like steroidal progestins, RWJ 26819 induces binding of the receptor to a progesterone response element in vitro, and stimulates gene expression in and proliferation of T47D human breast cancer cells. When administered to rabbits orally or subcutaneously, the compound induces histological changes in the uterine lining comparable to those induced by levonorgestrel. It also inhibits ovulation in monkeys. Though less potent in cells and in animal models than would be predicted from binding affinity alone, their enhanced selectivity suggests that they could be effectively used in a clinical setting. Most of the tetrahydropyridazines synthesized are progestin agonists or mixed agonists and antagonists in vitro; however, one compound with antagonist activity in the rabbit uterine transformation assay has been identified.

Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15-lipoxygenase.

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.

Bemoradan—a novel inhibitor of the rolipram-insensitive cyclic AMP phosphodiesterase from canine heart tissue

Canine cardiac muscle contains a type IV cyclic AMP (cAMP) phosphodiesterase (PDE) that is composed of two subtypes. One subtype is sensitive to rolipram inhibition (RSPDE), whereas the other is not inhibited significantly by rolipram (RIPDE). The RIPDE is inhibited by several cardiotonic agents operating by a PDE-inhibitory mechanism. Bemoradan [RWJ-22867; 7-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin -3(4H)-one], a novel, potent positive inotropic agent, demonstrated biphasic inhibition of the fraction III enzyme from canine cardiac muscle. Inhibition by rolipram of the RSPDE converted the IC50 curves of bemoradan, indolidan, pimobendan, and imazodan to sigmoidal, monophasic curves. Lineweaver-Burk analysis yielded competitive inhibition KI values of 0.023, 0.09, 0.065 and 0.60 microM, respectively, for these compounds. The cardiotonic compounds, however, were not potent inhibitors of the Type I and Type II cAMP PDEs found in canine ventricular muscle. The order of potency for inhibiting the RIPDE cAMP PDE subtype was bemoradan greater than pimobendan greater than indolidan greater than imazodan. Bemoradan is, therefore, a potent inhibitor of the cardiac muscle cAMP PDE which could, in part, be responsible for its cardiotonic activity.

A Convenient Synthesis of Mono- and Polyhalogenated Benzocyclanones

Abstract Benzocyclanones were mono- or dihalogenated on the aromatic ring with elemental halogen or N-halosuccinimide without solvent in an aluminum chloride slurry in good yield. This process is the most direct method for the synthesis of 5- or 7-halo, or 5,7-dihalotetralones and can be extended to indan-1-ones and benzocycloheptan-1-ones as well as to trihalogenated and to mixed halogenated products.

Synthesis and cardiotonic activity of 2,9-dihydro-6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)pyrazolo[4,3-b][1,4]benzoxazine

Abstract 2,9-Dihydro-6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)pyrazolo[4,3-b] [1,4]benzoxazine (1) is prepared in two steps from a precursor of bemoradan (2). The compound displays a maximum increase in cardiac force of 256% at 75 μg/kg intravenously in an anesthetized dog model and has an ED50 of 15 μg/kg.

N-Alkylated 2-Trifluoromethyl-4-quinolones by Addition of Base and an Alkylating Agent to 2-Trifluoroacetylaminoacetophenones

Abstract 2-Trifluoroacetylaminoacetophenones 1 are cyclized to N-alkyl-2-trifluoromethyl-4-quinolones 2 in one pot with concomitant N-alkylation in 40 to 74% yield using potassium hydroxide in acetone containing an alkylating agent.

2-aryl-1,2-dihydro-6,7-dimethoxyquinazoline-3-oxides with positive inotropic activity

Abstract A series of 2-aryl-1,2-dihydro-6,7-dimethoxyquinazoline-3-oxides was found to possess cardiotonic and blood pressure lowering activity in an open chest anesthetized dog model. Increases in cardiac force of greater than 150% at 10 mg/kg intraduodenally were recorded with the 2-phenyl analog.